학술논문
Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets
Document Type
article
Author
Kelsey M. Haas; Michael J. McGregor; Mehdi Bouhaddou; Benjamin J. Polacco; Eun-Young Kim; Thong T. Nguyen; Billy W. Newton; Matthew Urbanowski; Heejin Kim; Michael A. P. Williams; Veronica V. Rezelj; Alexandra Hardy; Andrea Fossati; Erica J. Stevenson; Ellie Sukerman; Tiffany Kim; Sudhir Penugonda; Elena Moreno; Hannes Braberg; Yuan Zhou; Giorgi Metreveli; Bhavya Harjai; Tia A. Tummino; James E. Melnyk; Margaret Soucheray; Jyoti Batra; Lars Pache; Laura Martin-Sancho; Jared Carlson-Stevermer; Alexander S. Jureka; Christopher F. Basler; Kevan M. Shokat; Brian K. Shoichet; Leah P. Shriver; Jeffrey R. Johnson; Megan L. Shaw; Sumit K. Chanda; Dan M. Roden; Tonia C. Carter; Leah C. Kottyan; Rex L. Chisholm; Jennifer A. Pacheco; Maureen E. Smith; Steven J. Schrodi; Randy A. Albrecht; Marco Vignuzzi; Lorena Zuliani-Alvarez; Danielle L. Swaney; Manon Eckhardt; Steven M. Wolinsky; Kris M. White; Judd F. Hultquist; Robyn M. Kaake; Adolfo García-Sastre; Nevan J. Krogan
Source
Nature Communications, Vol 14, Iss 1, Pp 1-27 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.